Hypertension affects one billion people worldwide and has become an increasing health burden in many societies. High blood pressure increases risks of stroke, myocardial infarction, congestive heart failure, and end-stage renal disease. Previous genetic screen studies discovered a number of genes that are associated with extreme forms of hypertension or hypotension disorders. However, it still remains unclear how the blood pressure level is being regulated in the general population. In addition, it is believed that hypertension is governed by multiple genetic factors, which makes it difficult to understand genetic etiology of hypertension using conventional approaches. Overall hypothesis of this application is that discovering rare functional variants from high or low blood pressure individuals will lead to better understanding of the genetic mechanism of blood pressure regulation, and eventually will lead to development of effective therapeutic interventions of hypertension. Here, I propose to use next-generation sequencing technique to interrogate genomes from a large cohort of high and low blood pressure individuals. Whole genome sequencing of several thousands of individuals still is a formidable task; therefore, we will capture and sequence coding regions of the genome (exome), which constitutes only 1% of the whole genome. Many groups reported successful application of whole exome sequencing technique for discovering disease-causing genetic variants. Our group accumulated extensive experiences and knowledge of the technique, developing a robust and efficient computational pipeline. Nonetheless, this is the first attempt to apply the next-generation sequencing technique to understand common complex disease. During the mentored phase, we will perform exome captured sequencing of high and low blood pressure groups. I expect that this effort will be completed during the mentored phase. To identify genes that are associated significantly with blood pressure trait, I will focus on detecting rare and functional genomic variants. These projects will be performed in the laboratory of Dr. Richard Lifton at Yale University, a renowned investigator with vast scientific contributions in understanding genetic causes of cardiovascular and renal diseases. He is committed to mentoring young investigators. As an independent investigator, I will incorporate statistical methods (1) to extend the understanding of genetic pathways that affect blood pressure trait; (2) to develop a novel method of assessing functional implication of genetic variants; and (3) to implement structural variant detection from exome sequencing data. At the conclusion of the study, we will have expanded understanding of blood pressure regulation and promising gene targets that can be tested independently using various experimental systems.